ONCOGENIC VIRUSES (Viruses which produce Cancer) History of Research: It has been known for a while that certain viruses induce or cause tumors. Tumor is a general term used to describe the uncontrollable growth of cells. Tumors can be Benign or Malignant (cancerous). Oncogenic viruses: many in animals, many examples: cat leukemia (Retroviruses). A few in humans. How do they produce tumors? a. Oncogenic virus enters the cell b. DNA of virus enters cells chromosome. If retrovirus, first, the RNA is converted to DNA (Provirus). The provirus DNA enters the cell. c. Virus has cancer causing gene= ONCOGENE TRANSFORMATION: cell becomes cancer cell. In 1976 (Varmus and Bishop from UCSF received Nobel Prize 1989). Oncogenes found in normal cells. (Same nucleotide sequence or genetic recipe) called PROTO-ONCOGENE. Most oncogenes are dominant genes. Whole lists of oncogenes now discovered for animal and a few for humans. We all have PROTO-ONCOGENES: Human’s total genome is 100,000 genes probably < 100 are protooncogenes. 40 discovered so far (50 Talaro). They have normal functions that are important. Now we know that all cancers are the result of an oncogene. How does a normal proto-oncogene becomes an oncogene Operon theory and the cancer universal theory: 1. Cell division operon: Shut off RNA polymerase ab regulator promoter operator Proto-oncogene liver enzyme prod. \------------\----\------------\-------------\-----------------------\----------------\----------\repressor protein no protein for cell division operon keeps cell division genes (proto-oncogenes) turned off. 2. How could a carcinogen or mutagen cause the proto-oncogene to be turned on out of control? * mutations in operator *mutations in regulator Also tumor suppressor genes = proteins that repair mutations or P53 gene which causes cells to die because have mutated beyond repair. 50 % of cancers have mutations in P53. Some mutant genes are the direct cause of cancer for example: mutant BRCA 1 -----> 85% of breast cancers have a mutation in this gene. Other cancers only result in cancer with certain environmental exposures. NAT gene------> enzyme that break down carcinogens including chemicals in tobacco smoke. cigarette smoke contains aromatic amines are highly mutagenic to DNA of breast cells. Women with a slow NAT gene (several versions of NAT) who also smoke are at very high risk of breast cancer. 3. How could a virus cause cancer? viruses carry their own oncogenes. are inserted into operon that turns on antibody production. insert and disrupt regulator or operator or carry gene that makes inducer to turn on proto-oncogene. 4. Inheritance: explains the genetic component of cancer too. inheritance of different numbers and kinds of proto-oncogenes. Some proto-oncogenes may be more easily disrupted than others. Familial breast cancer: runs in families < or = 40 years old. Animal oncogenic viruses: are good research tool. Human oncogenic viruses: Viruses generally do not cause cancer in humans, however, there are a couple that do. 1. Epstein-Barr Virus (EBV): Burkitt's lymphoma: Cancer of lymphoid tissue in the jaw. rare except in Central Africa where malaria is common. first thought that Burkitt's was transmitted by mosquito like malaria, but now we know that malaria just wipes out resistance and induces virus to cause cancer. 2. Human warts: 46 types: actually benign (harmless) tumor. Definitely cause by viruses. Human Papillomavirus involved in warts. Common plantar warts: HPV1 and 4 6 types involved in genital warts. family of viruses are all oncogenic in animals. DNA is inserted into chromosome. 3. Adult T-cell Leukemia: HTLV-1 retrovirus (human T lymphocyte virus 1) Endemic in Japan, The Caribbean, South and Central America in U.S. about 1 million people are infected. 1 person in 100 infected develop leukemia. HTLV-1 works differently than other viruses: other viruses: either insert a control gene next to a protooncogene and turn it on or insert their own oncogene. HTLV-1: its gene is the inducer that turns on cell's gene for making growth factor. 4. liver cancer: Hepatitis B chronic infections have a 200 times more likelihood to get liver cancer. Both very common in developing countries. in U.S. chronic hepatitis B only 0.1 %. Liver cancer also rare. China Chronic hep. B : 17% Parts of Africa : 90% liver cancer is the MOST COMMON cancer in the world. 5. Human Immunodeficiency Virus (HIV): It has been known for a while that HIV weakens the immune system (kills T-helper cells) and also allows the development of tumors and cancers. eg: Kaposi's sarcoma. Now it has been shown in some people that: HIV induces mixed cell lymphoma (B cells, T cells and macrophages all divide out of control). This occurs while still healthy no loss of immunity. HIV can sometimes insert DNA (after reverse transcription) into operon that turned on all the time.). 6. Other possible Human Oncogenic Viruses: There is less evidence it is mostly epidemiological. 1. 2. 3. 4. 5. EBV ------> Nasopharyngeal cancer RNA virus -----> breast cancer Genital Herpes ------> cervical cancer Genital warts -----> cervical cancer (specifically HPV-16) unknown virus -----> cervical cancer carried in sperm epidemiological evidence: sexually active females have higher cervical cancer rates unless they have sex with men with vasectomy. think that men are carrier of virus and is transmitted in sperm.